Preclinical Evaluation and a Pilot Clinical Positron Emission Tomography Imaging Study of [⁶⁸Ga]Ga-FAPI-FUSCC-II

Molecular Pharmaceutics, Год журнала: 2024, Номер 21(2), С. 904 - 915

Опубликована: Янв. 5, 2024

Fibroblast activation protein (FAP), a type II integral membrane serine protease, is promising target for tumor diagnosis and therapy. OncoFAP has been recently discovered PET imaging procedures various solid malignancies. In this study, we presented the development of manual radiolabeling preparation OncoFAP-based radiopharmaceuticals cancer imaging. A novel series [68Ga/177Lu]Ga/Lu-FAPI-FUSCC-I/II were produced with high radiochemical yields. [68Ga]Ga-FAPI-FUSCC-I/II [177Lu]Lu-FAPI-FUSCC-I/II stable in phosphate-buffered saline, fetal bovine serum, human serum at least 3 h. vitro cellular uptake blocking experiments implied that they had specificity to FAP. Additionally, low nanomolar IC50 values FAPI-FUSCC-II indicated it affinity The vivo biodistribution study mice bearing HT-1080-FAP tumors showed both exhibited specific uptake. [68Ga]Ga-FAPI-FUSCC-II higher tumor/nontarget ratio than [68Ga]Ga-FAPI-FUSCC-I [68Ga]Ga-FAPI-04. results ex accordance results. Clinical [68Ga]Ga-FAPI-FUSCC-II-PET/CT further demonstrated its favorable kinetics elevated reliable by primary (maximum standardized value (SUVmax), 12.17 ± 6.67) distant metastases (SUVmax, 9.24 4.28). summary, displayed increased retention compared [68Ga]Ga-FAPI-04, giving potential as tracer diagnostic malignant positive FAP expression.

Язык: Английский

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Imaging Molecular Targets and Metabolic Pathways in Breast Cancer for Improved Clinical Management: Current Practice and Future Perspectives

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(3), С. 1575 - 1575

Опубликована: Янв. 26, 2024

Breast cancer is the most frequently diagnosed and leading cause of cancer-related deaths worldwide. Timely decision-making that enables implementation appropriate therapy or therapies essential for achieving best clinical outcomes in breast cancer. While clinicopathologic characteristics immunohistochemistry have traditionally been used decision-making, these laboratory parameters may be difficult to ascertain equivocal due tumor heterogeneity. Tumor heterogeneity described as a phenomenon characterized by spatial temporal phenotypic variations characteristics. Spatial occur within lesions between at single time point while are seen evolve with time. Due limitations associated (which requires invasive biopsies), whole-body molecular imaging tools such standard-of-care [18F]FDG [18F]FES PET/CT indispensable addressing this conundrum. Despite their proven utility, methods often unable image myriad other pathways This has stimulated interest development novel radiopharmaceuticals targeting processes. In review, we discuss validated potential roles approaches. These approaches' relationships patient immunohistochemical well influence on management will discussed greater detail. paper also introduce utility PARP inhibitor-based non-invasive biomarkers expression/upregulation.

Язык: Английский

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Exploring the role of parthanatos in CNS injury: Molecular insights and therapeutic approaches

Journal of Advanced Research, Год журнала: 2024, Номер unknown

Опубликована: Май 1, 2024

Central nervous system (CNS) injury causes severe organ damage due to both resulting from the and subsequent cell death. However, there are currently no effective treatments for countering irreversible loss of function. Parthanatos is a poly (ADP-ribose) polymerase 1 (PARP-1)-dependent form programmed death that partly responsible neural Consequently, mechanism by which parthanatos promotes CNS has attracted significant scientific interest. Our review aims summarize potential role in its molecular pathophysiological mechanisms. Understanding related molecules crucial developing treatment strategies identifying important directions future in-depth research. (from Thanatos, personification according Greek mythology) type initiated overactivation PARP-1. This process triggers cascade reactions, including accumulation poly(ADP-ribose) (PAR), nuclear translocation apoptosis-inducing factor (AIF) after release mitochondria, massive DNA fragmentation caused migration inhibitory (MIF) forming complex with AIF. Secondary mechanisms, such as excitotoxicity oxidative stress-induced PARP-1, significantly exacerbate neuronal following initial mechanical CNS. Furthermore, not only associated but also interacts various other types focuses on latest research concerning pathway, particularly considering regulatory mechanisms functions damage. We highlight associations between different involved discuss therapeutic agents targeting pathway.

Язык: Английский

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The Role of Total-Body PET in Drug Development and Evaluation: Status and Outlook

Journal of Nuclear Medicine, Год журнала: 2024, Номер 65(Supplement 1), С. 46S - 53S

Опубликована: Май 1, 2024

Total-body PET, an emerging technique, enables high-quality simultaneous total-body dynamic PET acquisition and accurate kinetic analysis. It has the potential to facilitate study of multiple tracers while minimizing radiation dose improving tracer-specific imaging. This advancement holds promise for enhancing development clinical evaluation drugs, particularly radiopharmaceuticals. Multiple trials are using a scanner explore existing innovative However, challenges persist, along with opportunities, regard use in drug evaluation. Specifically, considerations relate role pharmacologic evaluations its integration into theranostic paradigm. In this review, state-of-the-art roles pharmaceutical research explored.

Язык: Английский

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Quinazoline-2,4(1 H,3 H)-dione Scaffold for development of a novel PARP-targeting PET probe for tumor imaging

European Journal of Nuclear Medicine and Molecular Imaging, Год журнала: 2024, Номер 51(13), С. 3840 - 3853

Опубликована: Июль 16, 2024

Язык: Английский

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Development of ^99mTc-Labeled Complexes with a Niraparib HYNIC Derivative for PARP-Positive Tumor Imaging

Molecular Pharmaceutics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

As an enzyme that plays important role in DNA repair, poly(ADP-ribose) polymerase-1 (PARP-1) has become a popular target for cancer therapy. Nuclear medicine molecular imaging technology, supplemented by radiolabeled PARP-1 inhibitors, can accurately determine the expression level of at lesion sites to help patients choose appropriate treatment plan. In this work, niraparib was modified with hydrazinonicotinamide (HYNIC) group generate ligand NPBHYNIC, which vitro affinity (IC50) 450.90 nM PARP-1. The NPBHYNIC labeled technetium-99m and six different coligands yield [99mTc]Tc-(X/tricine)-NPBHYNIC (X = TPPTS, TPPMS, PSA, PDA, NIC ISONIC). These complexes were hydrophilic exhibited good stability vitro, low levels these taken up nontarget organs tissues Kunming mice. Among complexes, [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC [99mTc]Tc-(NIC/tricine)-NPBHYNIC selected biodistribution HeLa tumor-bearing BALB/c nude mice 2 h post injection. results revealed tumor uptake (1.02 ± 0.07% ID/g) greater than (0.36 0.05% ID/g). Additionally, biodistribution, single-photon emission computed tomography/computed tomography (SPECT/CT) radioautography experiments, significantly reduced blocked group, indicating specificity. Therefore, it potential use as niraparib-based agent targets

Язык: Английский

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Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ

EJNMMI Radiopharmacy and Chemistry, Год журнала: 2025, Номер 10(1)

Опубликована: Янв. 10, 2025

Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PET tracer it features a strongly distinct chemotype compared frontrunners [18F]FluorThanatrace [18F]PARPi. was synthesised GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar (53 16 GBq/µmol) radiochemical purity (> 97%) subsequent preclinical evaluation. showed high stability formulation, human plasma, when incubated with liver microsomes. In vitro, similar specific uptake observed both PC3 cancer cells CHO-K1 Chinese hamster ovary cells. However, vivo studies using fertilised chicken eggs (in ovo model) revealed poor non-displaceable tumour accumulation PC3-derived xenografts, despite confirmed vascularisation expression. Rapid (10 min), less than 30% intact compound remaining 70 min post-injection. Although demonstrated metabolic binding suboptimal tumour-targeting properties pronounced metabolism were ovo. Therefore, further animal experiments mammalian models not indicated.

Язык: Английский

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Pilot Study of Nectin-4–Targeted PET Imaging Agent⁶⁸Ga-FZ-NR-1 in Triple-Negative Breast Cancer from Bench to First-in-Human

Journal of Nuclear Medicine, Год журнала: 2025, Номер unknown, С. jnumed.124.269024 - jnumed.124.269024

Опубликована: Фев. 13, 2025

Nectin cell adhesion molecule 4 (Nectin-4) is an emerging biomarker for cancer diagnosis and therapy. We developed a Nectin-4-targeted 68Ga-DOTA-Sar10-Nectin-4 (68Ga-FZ-NR-1) PET/CT radiotracer detecting Nectin-4 expression in tumor model triple-negative breast (TNBC) patients. Methods: A series of radiotracers-68Ga-FZ-NR-1, 68Ga-DOTA-polyethylene glycol 5-Nectin-4 (68Ga-FZ-NR-2), 10-Nectin-4 (68Ga-FZ-NR-3)-were synthesized, their targeting ability specificity were evaluated vitro vivo. In experiments performed the MDA-MB-468 (Nectin-4-positive) MDA-MB-231 (Nectin-4-negative) lines. imaging models was to assess Nectin-4-targeting radiotracers. After preclinical screening, 68Ga-FZ-NR-1 selected safety efficacy evaluation first-in-human trial TNBC Positive lesions biopsied analyzed by immunohistochemistry determine levels. Results: The 3 68Ga-labeled radiotracers exhibited high radiochemical purity, stability, strong affinity Nectin-4. uptake studies showed that effectively targeted cells, highest efficacy. model, taken up at higher rates than 68Ga-FZ-NR-2 68Ga-FZ-NR-3, it favorable pharmacokinetics profiles. thus subsequent clinical trials. identified tumors 9 patients with TNBC, which confirmed 18F-FDG PET/CT. Biopsy samples revealed positive corresponded areas expression. Conclusion: (68Ga-FZ-NR-1, 68Ga-FZ-NR-2, 68Ga-FZ-NR-3) evaluated. Preclinical demonstrated can identify preliminary study, used visualize Nectin-4-expressing immunohistochemistry. This provides noninvasive approach assessment potential basis development treatments TNBC.

Язык: Английский

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Imaging CDK4/6 Broaden Options of Breast Cancer Diagnostics with Positron Emission Tomography

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 13, 2025

This study developed a novel PET radiotracer to screen breast cancer patients sensitive CDK4/6 inhibitors, guiding personalized treatment. Two CDK4/6-targeting precursors were synthesized and evaluated in vitro vivo. Three cell lines─MCF-7, MDA-MB-231, MDA-MB-468─were selected based on decreasing sensitivity palbociclib. Compared [68Ga]Ga-DOTA-Hexa-CDKi, [68Ga]Ga-DOTA-Bua-CDKi clearly identified lines with high PET/CT imaging showed significantly higher uptake of (8.40 ± 0.85%ID/g) MCF-7 tumors 60 min after tracer injection, significant differences tumor among the three models (P < 0.05). Blocking assays demonstrated specific [68Ga]Ga-DOTA-Bua-CDKi. Biosafety tests validated its safety as diagnostic agent. highly targeting effective contrast models. To our knowledge, is one first radiotracers assess CDK inhibitor sensitivity, offering promise for evaluating patient responses inhibitors.

Язык: Английский

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Current Advances in PARP1‐Targeted Theranostics

Journal of Labelled Compounds and Radiopharmaceuticals, Год журнала: 2025, Номер 68(1-2)

Опубликована: Янв. 1, 2025

Poly (ADP-ribose) polymerase 1 (PARP1) plays critical roles in DNA repair, chromatin regulation, and cellular equilibrium, positioning it as a pivotal target for therapeutic interventions cancer central nervous system (CNS) disorders. PARP1 responds to oxidative stress damage through PARylation, influencing energy depletion, survival, inflammation, genomic regulation many biological scenarios. PARP inhibitors (PARPis) have demonstrated efficacy against cancers harboring defective homologous recombination repair pathways, notably those linked BRCA mutations. PARP1-targeted PET imaging enables patient stratification, treatment assessment, PARPi pharmacodynamic evaluation other pathophysiological conditions. Importantly, theranostics emerged both diagnostic applications multiple types of cancers, representing advancement personalized oncology. However, its application brain tumors is limited by the heterogeneous integrity blood barrier (BBB) blood-tumor barrier. Thus, development BBB-penetrant tracers remains an unmet need cancers. This review summarizes current landscape radiopharmaceuticals radioligands targeting PARP1, detailing their pharmacological characteristics potential clinical uses. Furthermore, this discusses that can cross BBB, underscoring neurooncology neurological

Язык: Английский

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